Inositol 1,4,5-Trisphosphate Receptor Type 3 Regulates Neuronal Growth Cone Sensitivity to Guidance Signals

Carmen Chan; Noriko Ooashi; Hiroki Akiyama; Tetsuko Fukuda; Mariko Inoue; Toru Matsu-Ura; Tomomi Shimogori; Katsuhiko Mikoshiba; Hiroyuki Kamiguchi

doi:10.1016/j.isci.2020.100963

Inositol 1,4,5-Trisphosphate Receptor Type 3 Regulates Neuronal Growth Cone Sensitivity to Guidance Signals

iScience. 2020 Mar 27;23(3):100963. doi: 10.1016/j.isci.2020.100963. Epub 2020 Mar 5.

Authors

Carmen Chan¹, Noriko Ooashi¹, Hiroki Akiyama², Tetsuko Fukuda¹, Mariko Inoue¹, Toru Matsu-Ura³, Tomomi Shimogori¹, Katsuhiko Mikoshiba⁴, Hiroyuki Kamiguchi⁵

Affiliations

¹ RIKEN Center for Brain Science, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan.
² Advanced Research Center for Human Sciences, Waseda University, Tokorozawa, Saitama 359-1192, Japan.
³ Department of Stem Cell Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
⁴ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
⁵ RIKEN Center for Brain Science, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan. Electronic address: hiroyuki.kamiguchi@riken.jp.

Abstract

During neurodevelopment, the growth cone deciphers directional information from extracellular guidance cues presented as shallow concentration gradients via signal amplification. However, it remains unclear how the growth cone controls this amplification process during its navigation through an environment in which basal cue concentrations vary widely. Here, we identified inositol 1,4,5-trisphosphate (IP₃) receptor type 3 as a regulator of axonal sensitivity to guidance cues in vitro and in vivo. Growth cones lacking the type 3 subunit are hypersensitive to nerve growth factor (NGF), an IP₃-dependent attractive cue, and incapable of turning toward normal concentration ranges of NGF to which wild-type growth cones respond. This is due to globally, but not asymmetrically, activated Ca²⁺ signaling in the hypersensitive growth cones. Remarkably, lower NGF concentrations can polarize growth cones for turning if IP₃ receptor type 3 is deficient. These data suggest a subtype-specific IP₃ receptor function in sensitivity adjustment during axon navigation.

Keywords: Biological Sciences; Cellular Neuroscience; Molecular Neuroscience; Neuroscience.